On the biomedical promise of cell penetrating peptides: limits versus prospects

The cell membrane poses a substantial hurdle to the use of pharmacologically active biomacromolecules that are not per se actively translocated into cells. An appealing approach to deliver such molecules involves tethering or complexing them with so-called cell penetrating peptides (CPPs) that are able to cross the plasma membrane of mammalian cells. The CPP approach is currently a major avenue in engineering delivery systems that are hoped to mediate the non-invasive import of problematic cargos into cells. The large number of different cargo molecules that have been efficiently delivered by CPPs ranges from small molecules to proteins and even liposomes and particles. With respect to the involved mechanism(s) there is increasing evidence for endocytosis as a major route of entry. Moreover, in terms of intracellular trafficking, current data argues for the transport to acidic early endosomal compartments with cytosolic release mediated via retrograde delivery through the Golgi apparatus and the endoplasmic reticulum. The focus of this review is to revisit the performance of cell penetrating peptides for drug delivery. To this aim we cover both accomplishments and failures and report on new prospects of the CPP approach. Besides a selection of successful case histories of CPPs we also review the limitations of CPP mediated translocation. In particular, we comment on the impact of (i) metabolic degradation, (ii) the cell line and cellular differentiation state dependent uptake of CPPs, as well as (iii) the regulation of their endocytic traffic by Rho-family GTPases. Further on, we aim at the identification of promising niches for CPP application in drug delivery. In this context, as inspired by current literature, we focus on three principal areas: (i) the delivery of antineoplastic agents, (ii) the delivery of CPPs as antimicrobials, and (iii) the potential of CPPs to target inflammatory tissues.